User:Christina Evans/Sandbox 1
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'''Effect of HCMV on MHC Class I''' | '''Effect of HCMV on MHC Class I''' | ||
| - | When a virus such as HCMV binds to MHC-I, the whole mechanism for alerting the immune system is disrupted. HCMV produces a glycoprotein called US2, through research done by Gewurz et. al. it was found that US2 binds to HLA-2, and this somehow sends MHC-I to the cytosol to be destroyed, instead of to the cell surface. A structural study found that US2 contains an immunoglobulin-like fold (Ig-like fold) that appears to play a role in evading the host’s immune system. An Ig-fold consists of two anti-parallel beta sheets of 110 amino acid residues connected by a disulfide bond. The Ig-like fold in US2 provides an area for extensive binding with the HLA molecule along one of the beta-sheets. Using pulse chase analysis, it was determined that one residue in particular was responsible for the dislocation of MHC-I to the cytoplasm. It has been found that a significant number of organ transplants result in patients infected with HCMV, because of the virus’s ability to establish latency. | + | |
| + | [[Image:HCMV_Model_Poster.jpg|thumb|left|Poster that outlines effect of HCMV on MHC-I, written by Burke, et. al. Based on research performed by Gewurz, et. al.]]When a virus such as HCMV binds to MHC-I, the whole mechanism for alerting the immune system is disrupted. HCMV produces a glycoprotein called US2, through research done by Gewurz et. al. it was found that US2 binds to HLA-2, and this somehow sends MHC-I to the cytosol to be destroyed, instead of to the cell surface. A structural study found that US2 contains an immunoglobulin-like fold (Ig-like fold) that appears to play a role in evading the host’s immune system. An Ig-fold consists of two anti-parallel beta sheets of 110 amino acid residues connected by a disulfide bond. The Ig-like fold in US2 provides an area for extensive binding with the HLA molecule along one of the beta-sheets. Using pulse chase analysis, it was determined that one residue in particular was responsible for the dislocation of MHC-I to the cytoplasm. It has been found that a significant number of organ transplants result in patients infected with HCMV, because of the virus’s ability to establish latency. | ||
Revision as of 09:25, 4 December 2012
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Description of Class I MHC
Class I major histocompatibility molecules are cell surface proteins that signal the presence of intracellular pathogens, such as viruses, to the host’s immune system. When viruses invade a host cell, they use the cell’s machinery to reproduce their nucleic acid and synthesize their proteins. Viral proteins, like cellular proteins, become targets for degradation and recycling, generating small portions of the viral proteins called peptides. Viral peptides of the right size can fit into the binding cleft of MHC-1 molecules, which are then displayed on the surface of the viral-infected cell. Cytotoxic T Lymphocytes (CTL), have receptors for foreign (viral) peptides complexed to MHC-1. When a CTL binds to a viral peptide-MHC-1 complex, the CTL secretes substances that lead to lysis and death of the infected cell, eventually clearing the infection. Thus, MHC-1 molecules function as an important warning system for the presence of intracellular infections. Viruses that develop a way to prevent expression of MHC-1 on the cell surface have a better chance of survival in the host.
History of Class I MHC
Major Histocompatibility proteins are encoded by a diverse set of genes that mediate transplant acceptance and rejection. MHC genes were discovered by scientists working on tissue rejection in inbred strains of mice and rabbits. Two scientists, E.E. Tyzzer and Clarence C. Little were interested in the genetic differences that control the immune response to transplanted tissues in mice. In 1916, they transplanted tumors from different strains of mice, and reported the acceptance and rejection of grafts between different strains. In a similar experiment, Bover found that tissues were accepted if the donor and recipient were identical twins. Bover concluded that rejection and acceptance of transplanted tissues is genetically controlled. In the 1940s, Peter Medawar working with rabbits confirmed that tissue graft rejection was triggered by an immune response. A few years later, George Snell ‘invented’ the congenic mouse strain. These mice were bred to be genetically identical, except at one locus. Snell called the locus that controlled tissue compatibility, histocompatibility genes2. Later studies revealed several closely linked histocompatibility genes that are located on the same chromosome, and became known as the MHC gene complex. In humans, MHC proteins are also called the Human Leucocyte Antigen, or HLA, and can be used interchangeably.
Stucture of Class I MHC
MHC-1 molecules are composed of two polypeptide or protein chains, an and . The alpha chain has three external domains designated α1, α2 and α3, a transmembrane region and a short cytoplasmic tail. The α1 and α2 domains interact to form the peptide-binding cleft composed of two α-helical regions and a bottom of antiparallel β strands. β-2 microglobulin associates noncovalently with the α3 domain and stabilizes the complex. Each chain is also being stabilized by a disulfide bond. The binding cleft can fit peptides 8-10 amino acids in length, and both viral and non-viral peptides can be expressed. Peptides are held into the groove by the amino acids that are located at the terminal ends of the peptide, these are called anchor residues. Because the MHC-1 molecule only interacts with the terminal residues, it does not matter what the non-terminal residues are. Therefore, a single MHC-1 molecule can present many different viral peptides, as long as the terminal amino acids are correct for that MHC-1 molecule.
Formation of MHC-I Molecules
MHC-1 molecules are synthesized in ribosomes anchored in the membrane of the endoplasmic reticulum (ER). In the ER, the MHC-I molecules first associate with a chaperone protein called calnexin. This helps the very large MHC-I molecule fold correctly into place, and helps it retain a partially folded state in the ER. When Calnexin is released, 2M binds to the α chain on MHC-I. Chaperone proteins, calreticulin and tapasin, stabilize the MHC-1 configuration until a peptide is loaded into the binding cleft. The peptide sits in a cleft formed by two α1 and 2 domains. The binding cleft is composed of two alpha helices that form walls and a β sheet that makes up the floor. Once the peptide is bound to MHC-I, Transporters Associated with Antigen Processing (TAP), tapasin, and calreticulin, dissociate from the MHC-1:peptide complex. This final, stable MHC-I:peptide complex is targeted to the surface of the cell via the Golgi apparatus.
Formation of Viral Peptide
When a virus injects its nucleic acid into a host cell, it uses the cell’s machinery to replicate its genome and synthesize its proteins. Because the viral proteins are being made within the host cell, the viral proteins can undergo recycling just like host cell proteins. Misfolded proteins are marked for destruction in the cytosol by the addition of a small molecule called, ubiquitin. Once ubiquitin is attached, the protein is sent to the proteasome. Proteosomes are large cylindrical structures with many proteolytic enzymes. In the presence of a virus, the proteasome cleaves proteins into peptides 8-10 residues long with the appropriate anchor residues ensuring a stable fit into the peptide binding cleft of the MHC-I molecule. The peptides are transported from the cytosol to the lumen of the Endoplasmic Reticulum (ER) via ER membrane proteins called Transporters Associated with Antigen Processing (TAP).
Function of MHC-I
The function of MHC-I is to alert the immune system that something is wrong with the host cell5. When an infected cell displays a viral peptide via MHC-I, Cytotoxic T Lymphocytes (CTLs) are attracted to it. CTLs use their T Cell Receptor (TCR) to bind to the viral peptide that is on display. Each CTL has its own TCR, which is able to detect its own foreign peptide. This variability among TCRs is made possible when the genes of a T cell shuffle to form its own, unique TCR. This ensures that many different peptides can be recognized by CTLs, so our body is thoroughly protected. TCRs that bind to self-peptides that are displayed on MHC-I are destroyed before they are allowed to travel around the body2. Once a TCR finds an MHC-I displaying its complementary peptide, the CTL binds strongly to the peptide. The interaction is strengthened with the help of a glycoprotein called, Cluster of Differentiation 8 (CD8) that is found on the surface of the CTL. When the TCR binds the peptide, CD8 binds to the MHC-I complex, forming a stronger bond between the CTL and the host cell1. After a strong bond has been made, the CTL is activated by signaling pathways and it starts to release perforin, a protein that makes pores in the surface of the infected host cell. The pores help granzymes, proteases that are released by the CTL, enter the infected host cell and attack the cell from the inside. CTLs also release cytokines, proteins that are secreted by one cell and cause an effect on another, that help the CTLs multiply, and activates them so they will start attacking other infected host cells3. None of this can occur, however, if MHC-I is not able to perform its function, and display viral peptides on the host cells surface.
Effect of HCMV on MHC Class I
